Hsiao B, Dweck D, Luetje C W
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101, USA.
J Neurosci. 2001 Mar 15;21(6):1848-56. doi: 10.1523/JNEUROSCI.21-06-01848.2001.
We examined the effect of zinc on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes as simple heteromers of alpha2, alpha3, or alpha4 and beta2 or beta4. Coapplication of zinc with low concentrations of acetylcholine (</=EC(10)) resulted in differential effects depending on receptor subunit composition. The alpha2beta2, alpha2beta4, alpha3beta4, alpha4beta2, and alpha4beta4 receptors exhibited biphasic modulation by zinc, with potentiation of the acetylcholine response occurring at 1-100 micrometer zinc and inhibition occurring at higher zinc concentrations. In contrast, alpha3beta2 receptors were only inhibited by zinc (IC(50) = 97 +/- 16 micrometer). The greatest potentiating effect of zinc was seen with alpha4beta4 receptors that were potentiated to 560 +/- 17% of the response to ACh alone, with an EC(50) of 22 +/- 4 micrometer zinc. Cadmium, but not nickel, was also able to potentiate alpha4beta4 receptors. Both zinc potentiation of alpha4beta4 receptors and zinc inhibition of alpha3beta2 receptors were voltage independent. The sensitivity of zinc potentiation of alpha4beta4 to diethylpyrocarbonate treatment and alterations in pH suggested the involvement of histidine residues. Zinc continued to inhibit alpha4beta4 and alpha3beta2 after diethylpyrocarbonate treatment. Application of a potentiating zinc concentration increased the response of alpha4beta2 and alpha4beta4 receptors to saturating ACh concentrations. The rate of Ach-induced desensitization of these receptors was unaffected by zinc. Our results reveal zinc potentiation as a new mode of neuronal nAChR modulation.
我们研究了锌对非洲爪蟾卵母细胞中表达的大鼠神经元烟碱型乙酰胆碱受体（nAChRs）的影响，这些受体为α2、α3或α4与β2或β4的简单异源二聚体。锌与低浓度乙酰胆碱（≤EC(10)）共同应用时，根据受体亚基组成会产生不同的效应。α2β2、α2β4、α3β4、α4β2和α4β4受体对锌呈现双相调节，在1 - 100微米锌浓度时乙酰胆碱反应增强，在更高锌浓度时则受到抑制。相比之下，α3β2受体仅受锌抑制（IC(50) = 97 ± 16微米）。锌对α4β4受体的增强作用最为显著，该受体对乙酰胆碱的反应增强至单独乙酰胆碱反应的560 ± 17%，锌的EC(50)为22 ± 4微米。镉而非镍也能够增强α4β4受体。α4β4受体的锌增强作用和α3β2受体的锌抑制作用均与电压无关。α4β4受体的锌增强作用对焦碳酸二乙酯处理和pH变化的敏感性表明组氨酸残基参与其中。焦碳酸二乙酯处理后，锌继续抑制α4β4和α3β2受体。应用增强性锌浓度可增加α4β2和α4β4受体对饱和乙酰胆碱浓度的反应。这些受体的乙酰胆碱诱导脱敏速率不受锌的影响。我们的结果揭示了锌增强作用是神经元nAChR调节的一种新模式。
